An over-reacting immune system is co-responsible for numerous chronic inflammatory diseases, such as, for example, rheumatoid arthritis, Crohn's disease, asthma and multiple sclerosis. Owing to an increased release of proinflammatory cytokines, damage to endogenous tissue structures results. The interplay of the innate and adaptive immune system is of central importance in this context (Akira et al., 2001). Modulation of the immune system by substances which interfere with the activation of cells of the innate and/or of the adaptive immune system has an anti-inflammatory action and can thus attenuate the pathological phenotype in the diseases mentioned by way of example above.
Innate immunity is based on the fact that microorganisms such as bacteria and viruses have certain inherent features by means of which they are recognized by the immune system and subsequently activate. Certain pathogen-associated molecular patterns (PAMPs) are recognized. PAMPs are recognized by the pattern recognition receptors (PRR), which also include toll-like receptors (TLR) (Janeway and Medzhitov, 2002). TLRs are homologues of the Drosophila receptor protein toll. Humans have ten different TLRs. TLR one and six are co-receptors for TLR2. TLR2 recognizes, inter alia, lipoproteins and lipopeptides. TLR3 recognizes double-stranded RNA. TLR4 recognizes, inter alia, LPS of gram-negative bacteria and lipoteichoic acid of gram-positive bacteria. TLR5 recognizes flagellin. TLR9 recognizes CpG motifs in bacterial DANN (O'Neill, 2006). Co-receptors can further modify the recognition capabilities of TLRs (Jiang et al., 2005).
IL-1/-18, TLR Signal Transduction
TLRs are related to IL-1/IL-18 cytokine receptors in signal transmission. IL-1 (“endogenous pyrogen”) strongly stimulates inflammation and induces fever. Members of the IL-1R/TLR superfamily have a TIR domain (toll/IL1 receptor). The TIR domain is approximately 200 amino acids long and contains three conserved sequence motifs. Proteins bearing TIR domains bind by means of a protein-protein interaction (O'Neill et al., 2005). The subclass one (IL-1R family) contains three Ig-like domains; the receptor is a heterodimer. These include the IL-1 receptors one and two, the co-receptor IL-1RAcP and the corresponding proteins of the IL-18 system. The subclass two (TLR family) contains leucine-rich motifs. Toll-like receptors form homo- or heterodimers.
After activation of the TLR or IL-1, -18 receptors by the appropriate ligands, a multistage signal cascade is set in motion. The TLR or IL-1/-18 receptor complex interacts with the adaptor protein MyD88 by means of TIR/TIR contacts. The IL-1 associated receptor kinase (IRAK-1) normally has Tollip (toll interacting protein) bound, which probably acts as an alleviating molecule (“silencer”). IRAK/Tollip binds to the active TLR/IL-1R complex. MyD88 displaces Tollip whereby IRAK1 and IRAK-4 are activated, very highly probably as a dimer by transphosphorylation. Active IRAK leaves the receptor and binds in the cytoplasm to the adapter molecule TRAF (Barton and Medzhitov, 2003). By means of TRAF, further proteins are ubiquitinylated. By means of an unknown mechanism, Ub-TRAF leads to the autophosphorylation of the S/T kinase TAK1 (a MAP kinase kinasekinase). TAK1 phosphorylates IκB (NF-κB activation) and MKK6. The latter is responsible for the activation of the MAP kinases p38 and JNK. NF-κB has been identified as a nuclear factor for the expression of the light antibody chain kappa in B cells, but is also involved in the regulation of many other genes. NF-κB is retained in the cytoplasm in the inactive state, where it is bound to the inhibitor IκB (Deng et al., 2000). Phosphorylation of IκB causes the inhibitor IkB to be proteolytically degraded and the transcription factor can migrate into the core. NF-κB is a heterodimer of the subunits p65 (Rel) and p50 (Bäuerle and Henkel, 1994). There are a number of members of this family which can interact in different ways. NF-κB on its own cannot induce transcription. For gene activation, transcriptional co-activators are necessary, such as, for example, p300 or CBT (Akira and Takeda, 2004).
The structures of the following patent applications form the structurally obvious prior art:
Benzyloxy-substituted quinazoline derivatives are mentioned in the following patent applications: WO 2006/076246 (Inhibitors of serine proteases), U.S. Pat. No. 5,962,458 (Inhibitors of VEGF receptor tyrosine kinase), U.S. Pat. No. 6,593,333 (Inhibitors of p38 kinase), U.S. Pat. No. 7,081,461 (Inhibitors of Aurora 2 kinase), WO 2004/105765 (Inhibitors of receptor tyrosine kinases), WO 2004/94410 (Inhibitors of Aurora A and/or Aurora B kinase). However, sulphoximine substituents for the benzyloxy radical are not disclosed. Alkoxy-substituted quinazoline derivatives are mentioned in the following patent applications: US 2006/0142570 (Kinase inhibitors), WO 2006/066795 (Kinase inhibitors), US 2005/101617 (ERB2 and EGFR inhibitors), WO 2005/013998 (Inhibitors of VEGF receptor tyrosine kinase), WO 2004/046101 (ERB2 and EGFR inhibitors), WO 2003/082831 (Inhibitors of ERB receptor tyrosine kinase), WO 2001/077085 (Inhibitors of VEGF receptor tyrosine kinase), WO 2000/047212 (Inhibitors of VEGF receptor tyrosine kinase), WO 98/13354 (Inhibitors of VEGF receptor tyrosine kinase), WO 97/30035 (Inhibitors of VEGF receptor tyrosine kinase). However, sulphoximine substituents for the alkoxy radical are not disclosed.
Starting from this prior art, the object of the present invention consists in preparing further structures for therapy, in particular for immunomodulation.
The object is achieved by sulphoximine-substituted compounds of the general formula (I),
in which    R1 represents            (i) a mono- or polysubstituted aryl or heteroaryl ring optionally identically or differently substituted by hydroxyl, —NR7R8, —NR6—C(O)—R12, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR7—SO2—R11, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms, or        (ii) a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, —NR6—C(O)R11, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR6—SO2—R11, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms, or        (iii) a C3-C8 cycloalkyl or heterocyclyl ring having 3 to 8 ring atoms and optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, —NR6—C(O)—R11, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR6—SO2—R11, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms,            R2 represents            (i) hydrogen,        (ii) hydroxyl, halogen, cyano, nitro, —CF3, —OCF3, —C(O)OR11, —C(O)OH, —C(O)NR7R8, —C(S)NR7R8, —NR7R8, —NR6—C(O)—R11, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR6—SO2—R11, or        (iii) a C1-C6-alkyl or C1-C6-alkoxy radical optionally identically or differently mono- or polysubstituted by halogen, hydroxyl, C1-C6-alkoxy, —CF3, —OCF3 or —NR7R8, or        (iv) a C3-C8-cycloalkyl ring optionally identically or differently mono- or polysubstituted by halogen, hydroxyl, C1-C6-alkoxy, —CF3, —OCF3, —NR7R8 and/or C1-C6-alkyl,            R3 represents            a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical, a C3-C7-cycloalkyl or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring, in each case itself optionally identically or differently mono- or polysubstituted by hydroxyl, —C(O)OR11, —C(O)NR7R8, —NR7R8, cyano, halogen, —CF3, C1-C6-alkoxy, —OCF3 and/or C1-C6-alkyl,            R4 represents            hydrogen, —SO2R11, —C(O)R11, —C(O)OR11, —C(O)NR7R8, —C(S)OR11, —C(S)NR7R8 or —R11,            X, Y independently of one another represents —O— or the group —NR5—,    A represents            (i) a bond or        (ii) an aryl or heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, —NR6—C(O)—R11, —C(O)NR7R8, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR6—SO2—R11, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms,            n represents 1-6,    R5 represents            (i) hydrogen,        (ii) a C1-C6-alkyl radical, C3-C8-cycloalkyl or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a heteroaryl ring, or        (iii) —C(O)—(C1-C6)-alkyl, —C(O)-phenyl, or —C(O)-benzyl, (ii) and (iii) optionally being identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkoxy and/or —OCF3,        or, if X represents —NR5—, alternatively X, R1 and R5 together form a 3- to 8-membered ring which optionally, in addition to the nitrogen atom, contains one or more further heteroatoms, is optionally identically or differently mono- or polysubstituted by hydroxyl, C1-C6-alkyl, C1-C6-alkoxy, —C(O)R11, —SO2R11, halogen or the group —NR8R9, optionally contains 1 to 3 double bonds and/or is optionally interrupted by one or more —C(O)— groups,            R6 represents hydrogen or a C1-C6-alkyl radical,    R7 and R8 independently of one another represent            (i) hydrogen and/or        (ii) a C1-C6-alkyl radical, C2-C6-alkenyl, C3-C8-cycloalkyl and/or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a heteroaryl ring, are optionally identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkoxy and/or —OCF3, or            R7 and R8 together with the nitrogen atom form a 5- to 7-membered ring, which optionally, in addition to the nitrogen atom, contains 1 or 2 further heteroatoms and which can be identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkyl, C1-C6-alkoxy and/or —OCF3,    R9 and R10 independently of one another represent hydrogen or a C1-C6-alkyl radical which is optionally identically or differently mono- or polysubstituted by hydroxyl,    R11 represents a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical, a C3-C8-cycloalkyl or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a heteroaryl ring, in each case optionally itself identically or differently mono- or polysubstituted by hydroxyl, halogen, cyano, nitro, —NR7R8, C1-C6-alkyl , —CF3, C1-C6-alkoxy and/or —OCF3,and their salts, diastereomers and enantiomers.
The following definitions underlie the invention:
Cn-Alkyl:
Monovalent, straight-chain or branched, saturated hydrocarbon radical having n carbon atoms.
A C1-C6 alkyl radical comprises, inter alia, for example:    methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-, iso-propyl-, iso-butyl-, sec-butyl, tert-butyl-, iso-pentyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl, neo-pentyl-, 1,1-dimethylpropyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-, 2,2-dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-dimethylbutyl-, 1,2-dimethylbutyl-.
A methyl, ethyl, propyl or isopropyl radical is preferred.
Cn-Alkenyl:
Monovalent, straight-chain or branched hydrocarbon radical having n carbon atoms and at least one double bond.
A C2-C6 alkenyl radical comprises, inter alia, for example:    vinyl-, allyl-, (E)-2-methylvinyl-, (Z)-2-methylvinyl-, homoallyl-, (E)-but-2-enyl-, (Z)-but-2-enyl-, (E)-but-1-enyl-, (Z)-but-1-enyl-, pent-4-enyl-, (E)-pent-3-enyl-, (Z)-pent-3-enyl-, (E)-pent-2-enyl-, (Z)-pent-2-enyl-, (E)-pent-1-enyl-, (Z)-pent-1-enyl-, hex-5-enyl-, (E)-hex-4-enyl-, (Z)-hex-4-enyl-, (E)-hex-3-enyl-, (Z)-hex-3-enyl-, (E)-hex-2-enyl-, (Z)-hex-2-enyl-, (E)-hex-1-enyl-, (Z)-hex-1-enyl-, isopropenyl-, 2-methylprop-2-enyl-, 1-methylprop-2-enyl-, 2-methylprop-1-enyl-, (E)-1-methylprop-1-enyl-, (Z)-1-methylprop-1-enyl-, 3-methylbut-3-enyl-, 2-methylbut-3-enyl-, 1-methylbut-3-enyl-, 3-methylbut-2-enyl-, (E)-2-methylbut-2-enyl-, (Z)-2-methylbut-2-enyl-, (E)-1-methylbut-2-enyl-, (Z)-1-methylbut-2-enyl-, (E)-3-methylbut-1-enyl-, (Z)-3-methylbut-1-enyl-, (E)-2-methylbut-1-enyl-, (Z)-2-methylbut-1-enyl-, (E)-1-methylbut-1-enyl-, (Z)-1-methylbut-1-enyl-, 1,1-dimethylprop-2-enyl-, 1-ethylprop-1-enyl-, 1-propylvinyl-, 1-isopropylvinyl-, 4-methylpent-4-enyl-, 3-methylpent-4-enyl-, 2-methylpent-4-enyl-, 1-methylpent-4-enyl-, 4-methylpent-3-enyl-, (E)-3-methylpent-3-enyl-, (Z)-3-methylpent-3-enyl-, (E)-2-methylpent-3-enyl-, (Z)-2-methylpent-3-enyl-, (E)-1-methylpent-3-enyl-, (Z)-1-methylpent-3-enyl-, (E)-4-methylpent-2-enyl-, (Z)-4-methylpent-2-enyl-, (E)-3-methylpent-2-enyl-, (Z)-3-methylpent-2-enyl-, (E)-2-methylpent-2-enyl-, (Z)-2-methylpent-2-enyl-, (E)-1-methylpent-2-enyl-, (Z)-1-methylpent-2-enyl-, (E)-4-methylpent-1-enyl-, (Z)-4-methylpent-1-enyl-, (E)-3-methylpent-1-enyl-, (Z)-3-methylpent-1-enyl-, (E)-2-methylpent-1-enyl-, (Z)-2-methylpent-1-enyl-, (E)-1-methylpent-1-enyl-, (Z)-1-methylpent-1-enyl-, 3-ethylbut-3-enyl-, 2-ethylbut-3-enyl-, 1-ethylbut-3-enyl-, (E)-3-ethylbut-2-enyl-, (Z)-3-ethylbut-2-enyl-, (E)-2-ethylbut-2-enyl-, (Z)-2-ethylbut-2-enyl-, (E)-1-ethylbut-2-enyl-, (Z)-1-ethyl-but-2-enyl-, (E)-3-ethylbut-1-enyl-, (Z)-3-ethylbut-1-enyl-, 2-ethylbut-1-enyl-, (E)-1-ethylbut-1-enyl-, (Z)-1-ethylbut-1-enyl-, 2-propylprop-2-enyl-, 1-propylprop-2-enyl-, 2-isopropylprop-2-enyl-, 1-isopropylprop-2-enyl-,(E)-2-propylprop-1-enyl-, (Z)-2-propylprop-1-enyl-, (E)-1-propylprop-1-enyl-, (Z)-1-propylprop-1-enyl-, (E)-2-isopropylprop-1-enyl-, (Z)-2-isopropylprop-1-enyl-, (E)-1-isopropylprop-1-enyl-, (Z)-1-isopropylprop-1-enyl-, (E)-3,3-dimethylprop-1-enyl-, (Z)-3,3-dimethylprop-1-enyl-, 1-(1,1-dimethylethyl)ethenyl.
A vinyl or allyl radical is preferred.
Cn-Alkynyl:
Monovalent, straight-chain or branched hydrocarbon radical having n carbon atoms and at least one triple bond.
A C2-C6 alkynyl radical comprises, inter alia, for example:    ethynyl-, prop-1-ynyl-, prop-2-ynyl-, but-1-ynyl-, but-2-ynyl-, but-3-ynyl-, pent-1-ynyl-, pent-2-ynyl-, pent-3-ynyl-, pent-4-ynyl-, hex-1-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl-, hex-5-ynyl-, 1-methylprop-2-ynyl-, 2-methylbut-3-ynyl-, 1-methylbut-3-ynyl-, 1-methylbut-2-ynyl-, 3-methylbut-1-ynyl-, 1-ethylprop-2-ynyl-, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl-, 1-ethylbut-3-ynyl-, 1-ethylbut-2-ynyl-, 1-propylprop-2-ynyl-, 1-isopropylprop-2-ynyl-, 2,2-dimethylbut-3-ynyl-, 1,1-dimethylbut-3-ynyl-, 1,1-di-methylbut-2-ynyl- or a 3,3-dimethylbut-1-ynyl-.
An ethynyl-, prop-1-ynyl- or prop-2-ynyl- radical is preferred.
Cn-Cycloalkyl:
Monovalent, cyclic hydrocarbon ring having n carbon atoms.
C3-C7-Cycloalkyl ring comprises:    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
A cyclopropyl, cyclobutyl, cyclopentyl or a cyclohexyl ring is preferred.
Cn-Alkoxy:
Straight-chain or branched Cn-alkyl ether radical of the formula —OR with R=alkyl.
Aryl
Aryl is a monovalent, aromatic ring system without a heteroatom.
C6-aryl is equal to phenyl. C10-aryl ist equal to naphthyl.
Unless stated otherwise, aryl comprises only phenyl and napthyl.
Phenyl is preferred.
Heteroatoms
Heteroatoms are to be understood as meaning oxygen, nitrogen or sulphur atoms.
Heteroaryl
Heteroaryl is a monovalent, aromatic ring system having at least one heteroatom different from a carbon. Heteroatoms which can occur are nitrogen atoms, oxygen atoms and/or sulphur atoms. The bond valency can be on any desired aromatic carbon atom or on a nitrogen atom.
Unless stated otherwise, heteroaryl comprises only monocyclic and bicyclic rings.
A monocyclic heteroaryl ring according to the present invention has 5 or 6 ring atoms.
Heteroaryl rings having 5 ring atoms comprise, for example, the rings:    thienyl, thiazolyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl and thiadiazolyl.
Heteroaryl rings having 6 ring atoms comprise, for example, the rings:    pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
A bicyclic heteroaryl ring according to the present invention has 9 or 10 ring atoms.
Heteroaryl rings having 9 ring atoms comprise, for example, the rings:    phthalidyl, thiophthalidyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, indolonyl, isoindolonyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl.
Heteroaryl rings having 10 ring atoms comprise, for example, the rings: isoquinolinyl-, quinolinyl-, benzoxazinonyl-, phthalazinonyl, quinolonyl-, isoquinolon-yl-, quinazolinyl-, quinoxalinyl-, cinnolinyl-, phthalazinyl-, 1,7- or 1,8-naphthyridinyl-, quinolinyl-, isoquinolinyl-, quinazolinyl- or quinoxalinyl-.
Monocyclic heteroaryl rings having 5 or 6 ring atoms are preferred.
Heterocyclyl
Heterocyclyl within the meaning of the invention is a completely hydrogenated heteroaryl (completely hydrogenated heteroaryl=saturated heterocyclyl), i.e. a non-aromatic ring system having at least one heteroatom different from a carbon.
Heteroatoms which can occur are nitrogen atoms, oxygen atoms and/or sulphur atoms. The bond valency can be on any desired carbon atom or on a nitrogen atom.
Heterocyclyl ring having 3 ring atoms comprises, for example:    aziridinyl.
Heterocyclyl ring having 4 ring atoms comprises, for example:    azetidinyl, oxetanyl.
Heterocyclyl rings having 5 ring atoms comprise, for example, the rings:    pyrrolidinyl, imidazolidinyl, pyrazolidinyl and tetrahydrofuranyl.
Heterocyclyl rings having 6 ring atoms comprise, for example, the rings:    piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and thiomorpholinyl
Heterocyclyl ring having 7 ring atoms comprises, for example:    azepanyl, oxepanyl, [1,3]-diazepanyl, [1,4]-diazepanyl.
Heterocyclyl ring having 8 ring atoms comprises, for example:    oxocanyl, azocanyl
Unless stated otherwise, heterocyclyl denotes a heterocyclyl ring having 3 to 8 ring atoms.
Halogen
The designation halogen comprises fluorine, chlorine, bromine and iodine.
Compounds of the general formula (I) form a preferred subgroup, in which    R1 represents            (i) an aryl or heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, cyano, halogen, C1-C6-alkoxy, —NR6—C(O)R11, —OCF3, —CF3, C1-C6-alkyl, or        (ii) a C1-C6-alkyl radical optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, cyano, halogen, C1-C6-alkoxy, —NR6—C(O)R11, —OCF3, —CF3, C1-C6-alkyl, or        (iii) a C3-C8 cycloalkyl or heterocyclyl ring having 3 to 8 ring atoms and optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl,            R2 represents hydrogen, halogen, cyano, —C(O)OR11, —C(O)OH, —C(O)NR7R8or a C1-C6-alkyl or C1-C6-alkoxy radical optionally identically or differently mono- or polysubstituted by halogen, hydroxyl, C1-C6-alkoxy, —CF3, —OCF3 or —NR7R8     R3 represents a C1-C6-alkyl radical or a C3-C7-cycloalkyl ring, optionally itself identically or differently mono- or polysubstituted by hydroxyl, —C(O)OR11, —C(O)NR7R8, —NR7R8, cyano, halogen, —CF3, C1-C6-alkoxy, —OCF3 and/or C1-C6-alkyl,    R4 represents            hydrogen, —SO2R11, —C(O)OR11, —C(O)NR7R8,            X represents the group —NR5—,    Y represents —O— or the group NR5,    A represents            (i) a bond or        (ii) an aryl or heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, —C(O)NR7R8, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms,            n represents 1-5,    R5 represents hydrogen, a C1-C6-alkyl radical, a C3-C8-cycloalkyl ring or —C(O)—(C1-C6)-alkyl, are in each case optionally identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkoxy and/or —OCF3,    R7 and R8 independently of one another represent            (i) hydrogen and/or        (ii) a C1-C6-alkyl radical, a C3-C8-cycloalkyl and/or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a heteroaryl ring, are optionally identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkoxy and/or —OCF3,            R11 represents a C1-C3-alkyl, a C3-C8-cycloalkyl or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a heteroaryl ring, in each case optionally itself identically or differently mono- or polysubstituted by hydroxyl, halogen, cyano, nitro, —NR7R8, C1-C6-alkyl , —CF3, C1-C6-alkoxy and/or —OCF3,and their salts, diastereomers and enantiomers.
Compounds of the general formula (I) form a particularly preferred subgroup, in which    R1 represents an aryl or heteroaryl ring optionally substituted by hydroxyl, or            represents a C1-C6-alkyl radical or C3-C8 cycloalkyl ring optionally identically or differently mono- or polysubstituted by —NR7R8 or C1-C6-alkoxy            R2 represents hydrogen, halogen, —C(O)OR11, —C(O)OH or a C1-C6-alkoxy radical,    R3 represents a C1-C3-alkyl radical    R4 represents hydrogen, —SO2R11 or —C(O)OR11,    X represents —NH—,    Y represents —O—,    A represents a bond or an aryl ring,    n represents 1-4,    R7 and R8 independently of one another represent a C1-C6-alkyl radical    R11 represents a C1-C3-alkyl radical or an aryl ring, in each case optionally itself substituted by nitro,and their salts, diastereomers and enantiomers.
Compounds of the general formula (I) form a likewise particularly preferred subgroup, in which                R1 represents                    (i) a phenyl or monocyclic heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR6—C(O)—R11, cyano, C1-C6-alkyl, or            (ii) a C1-C6-alkyl radical optionally identically or differently mono or polysubstituted by hydroxyl, —NR7R8, C1-C6-alkoxy and/or C3-C6-cycloalkyl, or            (iii) a C3-C8 cycloalkyl ring.                        R2 represents hydrogen, halogen, cyano, —C(O)OR11, —C(O)OH, or a C1-C6-alkoxy radical,        R3 represents a C1-C6-alkyl radical        R4 represents hydrogen, —SO2R11 or —C(O)OR11,        X represents —NH—,        Y represents —O—, or —NH—        A represents a bond or a phenyl or monocyclic heteroaryl ring,        n represents 1-4,        R6 represents hydrogen,        R7 and R8 represent a C1-C6-alkyl radical,        R11 represents a C1-C6-alkyl radical or phenyl ring, in each case optionally itself substituted by nitro,        and their salts, diastereomers and enantiomers.        
In the general formula (I), R1 can represent    (i) an aryl or heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, —NR6—C(O)—R11, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR7—SO2—R11, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms, or    (ii) a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical, optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, —NR6—C(O)R11, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR6—SO2—R11, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms, or    (iii) a C3-C8 cycloalkyl or heterocyclyl ring having 3 to 8 ring atoms and optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, —NR6—C(O)—R11, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR6—SO2—R11, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms.
Preferably, R1 represents    (i) an aryl or heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, cyano, halogen, C1-C6-alkoxy, —NR6—C(O)R11, —OCF3, —CF3, C1-C6-alkyl, or    (ii) a C1-C6-alkyl radical optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, cyano, halogen, C1-C6-alkoxy, —NR6—C(O)R11, —OCF3, —CF3, C1-C6-alkyl, or    (iii) a C3-C8 cycloalkyl or heterocyclyl ring having 3 to 8 ring atoms and optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl.
Particularly preferably, R1 represents:    (i) a phenyl or monocyclic heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR6—C(O)—R|, cyano, C1-C6-alkyl, or    (ii) a C1-C6-alkyl radical optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, C1-C6-alkoxy and/or C3-C6-cycloalkyl, or    (iii) a C3-C8 cycloalkyl ring.
Particularly preferably, R1 also represents:    an aryl or heteroaryl ring optionally substituted by hydroxyl, or a C1-C6-alkyl radical or C3-C8 cycloalkyl ring optionally identically or differently mono- or polysubstituted by —NR7R8 or C1-C6-alkoxy.
In the general formula (1), R2 can represent    (i) hydrogen,    (ii) hydroxyl, halogen, cyano, nitro, —CF3, —OCF3, —C(O)OR11, —C(O)OH, —C(O)NR7R8, —C(S)NR7R8, —NR7R8, —NR6—C(O)—R11, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR6—SO2—R11, or    (iii) a C1-C6-alkyl or C1-C6-alkoxy radical optionally identically or differently mono- or polysubstituted by halogen, hydroxyl, C1-C6-alkoxy, —CF3, —OCF3 or —NR7R8, or    (iv) a C3-C8-cycloalkyl ring optionally identically or differently mono- or polysubstituted by halogen, hydroxyl, C1-C6-alkoxy, —CF3, —OCF3, —NR7R8 and/or C1-C6-alkyl.
Preferably, R2 represents:    hydrogen, halogen, cyano, —C(O)OR11, —C(O)OH, —C(O)NR7R8 or a C1-C6-alkyl or C1-C6-alkoxy radical optionally identically or differently mono- or polysubstituted by halogen, hydroxyl, C1-C6-alkoxy, —CF3, —OCF3 or —NR7R8.
Particularly preferably, R2 represents:    hydrogen, halogen, cyano, —C(O)OR11, —C(O)OH or a C1-C6-alkoxy radical.
Particularly preferably, R2 also represents    hydrogen, halogen, —C(O)OR11, —C(O)OH or a C1-C6-alkoxy radical.
In the general formula (1), R3 can represent    a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical, a C3-C7-cycloalkyl or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring, in each case optionally itself identically or differently mono- or polysubstituted by hydroxyl, —C(O)OR11, —C(O)NR7R8, —NR7R8, cyano, halogen, —CF3, C1-C6-alkoxy, —OCF3 and/or C1-C6-alkyl.
Preferably, R3 represents    a C1-C6-alkyl radical or a C3-C7-cycloalkyl ring, optionally itself identically or differently mono- or polysubstituted by hydroxyl, —C(O)OR11, —C(O)NR7R8, —NR7R8, cyano, halogen, —CF3, C1-C6-alkoxy, —OCF3 and/or C1-C6-alkyl,
Particularly preferably, R3 represents    a C1-C3-alkyl radical
In the general formula (I) R4 can represent    hydrogen, —SO2R11, —C(O)R11, —C(O)OR11, —C(O)NR7R8, —C(S)OR11, —C(S)NR7R8 or —R11,
Preferably, R4 represents    hydrogen, —SO2R11, —C(O)OR11 or —C(O)NR7R8 
Particularly preferably, R4 represents:    hydrogen, —SO2R11 or —C(O)OR11 
In the general formula (I), X and Y independently of one another represent:    —O— or the group —NR5—.
Preferably, X represents the group —NR5—.
Particularly preferably, X represents —NH—.
Preferably, Y represents —O—, or the group —NR5—.
Particularly preferably, Y represents —O— or —NH—.
Exceptionally preferably, Y represents —O—.
In the general formula (I), A can represent    (i) a bond or    (ii) an aryl or heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, —NR6—C(O)—R11—C(O)NR7R8, —NR6—C(O)—OR11, —NR6—C(O)—NR7R8, —NR6—SO2—R11, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms.
Preferably, A represents:    (i) a bond or    (ii) an aryl or heteroaryl ring optionally identically or differently mono- or polysubstituted by hydroxyl, —NR7R8, cyano, halogen, C1-C6-alkoxy, —OCF3, —CF3, C1-C6-alkyl, C3-C6-cycloalkyl and/or heterocyclyl having 3 to 8 ring atoms,
Particularly preferably, A represents:    a bond or a phenyl or monocyclic heteroaryl ring.
Particularly preferably, A also represents:    a bond or a phenyl ring.
In the general formula (I), n can represent 1-6.
Preferably, n represents 1-5.
Particularly preferably, n represents 1-4.
In the general formula (I), R5 can represent    (i) hydrogen,    (ii) a C1-C6-alkyl radical, C3-C8-cycloalkyl or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a heteroaryl ring, or    (iii) —C(O)—(C1-C6)-alkyl, —C(O)-phenyl, or —C(O)-benzyl, and (ii) and (iii) are optionally identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkoxy and/or —OCF3, or, if X represents —NR5—, alternatively X, R1 and R5 together form a 3- to 8-membered ring which optionally, in addition to the nitrogen atom, contains one or more further heteroatoms, is optionally identically or differently mono- or polysubstituted by hydroxyl, C1-C6-alkyl, C1-C6-alkoxy, —C(O)R11, —SO2R11, halogen or the group —NR8R9, optionally contains 1 to 3 double bonds and/or is optionally interrupted by one or more —C(O)— groups,
Preferably, R5 represents:    hydrogen, a C1-C6-alkyl radical, a C3-C8-cycloalkyl ring or —C(O)—(C1-C6)-alkyl, are in each case optionally identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkoxy and/or —OCF3.
In the general formula (I), R6 can represent    hydrogen or a C1-C6-alkyl radical.
Particularly preferably, R6 represents hydrogen.
In the general formula (I), R7 and R8 independently of one another can represent    (i) hydrogen and/or    (ii) a C1-C6-alkyl radical, C2-C6-alkenyl, C3-C8-cycloalkyl and/or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a heteroaryl ring, are optionally identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkoxy and/or —OCF3, or    R7 and R8 together with the nitrogen atom form a 5- to 7-membered ring, which optionally in addition to the nitrogen atom contains 1 or 2 further heteroatoms and which can be identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkyl, C1-C6-alkoxy and/or —OCF3.
Preferably, R7 and R8 independently of one another represent:    (i) hydrogen and/or    (ii) a C1-C6-alkyl radical, a C3-C8-cycloalkyl and/or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a heteroaryl ring, are optionally identically or differently mono- or polysubstituted by hydroxyl, —NR9R10, cyano, halogen, —CF3, C1-C6-alkoxy and/or —OCF3.
Particularly preferably, R7 and R8 independently of one another represent:    a C1-C6-alkyl radical.
In the general formula (I), R9 and R10 independently of one another represent:    hydrogen or a C1-C6-alkyl radical, which is optionally identically or differently mono- or polysubstituted by hydroxyl,
In the general formula (I), R11 can represent    for a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical, a C3-C8-cycloalkyl or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a heteroaryl ring, in each case optionally itself identically or differently mono- or polysubstituted by hydroxyl, halogen, cyano, nitro, —NR7R8, C1-C6-alkyl , —CF3, C1-C6-alkoxy and/or —OCF3.
Preferably, R11 represents    a C1-C3-alkyl, a C3-C8-cycloalkyl or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a heteroaryl ring,    in each case optionally itself identically or differently mono- or polysubstituted by hydroxyl, halogen, cyano, nitro, —NR7R8, C1-C6-alkyl , —CF3, C1-C6-alkoxy and/or —OCF3.
Particularly preferably, R11 represents:    for a C1-C3-alkyl radical or a phenyl ring, in each case optionally itself substituted by nitro.
All compounds which result by any possible combination of the abovementioned possible, preferred and particularly preferred meanings of the substituents are likewise to be regarded as covered by the present invention.
Particular embodiments of the invention moreover consist in compounds which result by combination of the meanings for the substituents directly disclosed in the examples.
The salts of the compounds are likewise to be regarded as covered by the present invention.
The formulation of the compounds according to the invention to give pharmaceutical preparations is carried out in a manner known per se, by converting the active compound or compounds into the desired administration form using the excipients customary in galenics.
Excipients which can be used here are, for example, vehicles, fillers, disintegrants, binders, moisturizers, lubricants, absorbents and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, taste corrigents, colourants, preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers. Reference is to be made here to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).
The pharmaceutical formulations can be present    in solid form, for example as tablets, coated tablets, pills, suppositories, capsules, transdermal systems or    in semi-solid form, for example as ointments, creams, gels, suppositories, emulsions or    in liquid form, for example as solutions, tinctures, suspensions or emulsions.
Excipients within the meaning of the invention can be, for example, salts, saccharides (mono-, di-, tri-, oligo-, and/or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and their derivatives, where the excipients can be of natural origin or can be obtained synthetically or partially synthetically.
Tablets, coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions, in particular, are suitable for oral or peroral administration. Suspensions, emulsions and especially solutions, in particular, are suitable for parenteral administration.
On account of their anti-inflammatory and in addition immunosuppressive action, the compounds of the general formula (I) according to the invention can be used for local and systemic administration as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans:    (i) Pulmonary diseases which involve inflammatory, allergic and/or proliferative processes:            Chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma        Bronchitis of varying genesis        Adult respiratory distress syndrome (ARDS), acute respiratory distress syndrome        Bronchiectasis        All forms of restrictive pulmonary diseases, especially allergic alveolitis,        Pulmonary oedema, in particular allergic        Sarcoidosis and granulomatosis, in particular Boeck disease            (ii) Rheumatic diseases/autoimmune diseases/joint diseases, which involve inflammatory, allergic and/or proliferative processes:            All forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, rheumatic polymyalgia, Behcet's disease        Reactive arthritis        Inflammatory soft-tissue diseases of other genesis        Arthritic symptoms in degenerative joint diseases (arthroses)        Vitiligo        Collagenoses of any origin, e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis-Sjögren's syndrome, Still's disease, Felty's syndrome        Sarcoidoses and granulomatoses        Soft tissue rheumatism            (iii) Allergies or pseudoallergic diseases, which involve inflammatory, and/or proliferative processes:            All forms of allergic reactions, e.g. Quincke's oedema, hayfever, insect bite, allergic reactions to medicaments, blood derivatives, contrast agents etc., anaphylactic shock, urticaria, allergic and irritative contact dermatitis, allergic vascular diseases        Allergic vasculitis            (iv) Vascular inflammation (vasculitis)            Panarteritis nodosa, temporal arteritis, nodal fever        Polyarteritis nodosa        Wegener's granulomatosis        Giant cell arteritis            (v) Dermatological diseases which involve inflammatory, allergic and/or proliferative processes:            Atopic dermatitis (especially in children)        All forms of eczema such as, for example, atopic eczema (esp. in children)        Exanthema of any genesis or dermatoses        Psoriasis and parapsoriasis disorder        Pityriasis rubra pilaris        Erythematous diseases caused by different noxae, e.g. rays, chemicals, burns etc.        Bullous dermatoses such as, for example, autoimmune pemphigus vulgaris, bullous pemphigoid        Diseases of the lichenoid type,        Pruritus (e.g. of allergic genesis)        Rosacea disorder        Stevens-Johnson syndrome        Manifestation of vascular diseases        Hair loss such as alopecia areata        Cutaneous lymphoma            (vi) Renal diseases which involve inflammatory, allergic and/or proliferative processes:            Nephrotic syndrome        All nephrites, e.g. glomerulonephritis            (vii) Hepatic diseases which involve inflammatory, allergic and/or proliferative processes:            acute hepatitis of varying origin        chronic aggressive and/or chronic intermittent hepatitis            (viii) Gastrointestinal diseases which involve inflammatory, allergic and/or proliferative processes:            regional enteritis (Crohn's disease)        ulcerative colitis        gastroenteritis of varying origin, e.g. endemic sprue            (ix) Eye diseases which involve inflammatory, allergic and/or proliferative processes:            allergic keratitis, uveitis, iritis,        conjunctivitis        blepharitis        optical nerve neuritis        chorioiditis        sympathetic ophthalmia            (x) Diseases of the otorhinolaryngological region, which involve inflammatory, allergic and/or proliferative processes:            allergic rhinitis, hayfever        external otitis, e.g. caused by contact eczema            (xi) neurological diseases which involve inflammatory, allergic and/or proliferative processes:            cerebral oedema, especially allergic cerebral oedema        multiple sclerosis        acute encephalomyelitis        meningitis, especially allergic        Guillain-Barre syndrome        Alzheimer's disease            (xii) Blood diseases which involve inflammatory, allergic and/or proliferative processes, such as, for example: Hodgkin's disease or non-Hodgkin's lymphoma, thrombocytaemias, erythrocytoses            Acquired haemolytic anaemia        Idiopathic thrombocytopenia        Idiopathic granulocytopenia            (xiii) Oncoses which involve inflammatory, allergic and/or proliferative processes            Acute lymphatic leukaemia        Malignant lymphoma        Lymphogranulomatoses        Lymphosarcomas            (xiv) Endocrine diseases which involve inflammatory, allergic and/or proliferative processes such as, for example:            Endocrine orbitopathy        De Quervain thyroiditis        Hashimoto's thyroiditis        Basedow's disease        Granulomatous thyroiditis        Lymphadenoid goitre        Autoimmune adrenalitis        Diabetes mellitus, in particular type 1 diabetes        Endometriosis            (xv) Organ and tissue transplants, graft-versus-host disease    (xvi) Severe states of shock, e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
One subject of the invention is the use of the compounds of the general formula (I) according to the invention for the production of a medicament.
A further subject of the invention is the use of the compounds according to the invention for the treatment of diseases which involve inflammatory, allergic and/or proliferative processes.